The present invention relates to novel compounds and methods for the treatment of glaucoma and ocular hypertension. In particular, the present invention relates to the use of certain 13-oxa analogs of F, D, and E series prostaglandins to treat glaucoma and ocular hypertension.
Glaucoma is a progressive disease which leads to optic nerve damage and, ultimately, total loss of vision. The causes of this disease have been the subject of extensive studies for many years, but are still not fully understood. The principal symptom of and/or risk factor for the disease is elevated intraocular pressure or ocular hypertension due to excess aqueous humor in the anterior chamber of the eye.
The causes of aqueous humor accumulation in the anterior chamber are not fully understood. It is known that elevated intraocular pressure ("IOP") can be at least partially controlled by administering drugs which either reduce the production of aqueous humor within the eye, such as beta-blockers and carbonic anhydrase inhibitors, or increase the outflow of aqueous humor from the eye, such as miotics and sympathomimetics.
Most types of drugs conventionally used to treat glaucoma have potentially serious side effects. Miotics such as pilocarpine can cause blurring of vision and other visual side effects, which may lead either to decreased patient compliance or to termination of therapy. Systemically administered carbonic anhydrase inhibitors can also cause serious side effects such as nausea, dyspepsia, fatigue, and metabolic acidosis, which side effects can affect patient compliance and/or necessitate the termination of treatment. Another type of drug, beta-blockers, have increasingly become associated with serious pulmonary side effects attributable to their effects on beta-2 receptors in pulmonary tissue. Sympathomimetics, on the other hand, may cause tachycardia, arrhythmia and hypertension. Recently, certain prostaglandins and prostaglandin derivatives have been described in the art as being useful in reducing intraocular pressure. Typically, however, prostaglandin therapy for the treatment of elevated intraocular pressure is attended by undesirable side-effects, such as irritation and hyperemia of varying severity and duration. There is therefore a continuing need for therapies which control elevated intraocular pressure associated with glaucoma without the degree of undesirable side-effects attendant to most conventional therapies.
Prostaglandins are metabolite derivatives of arachidonic acid. Arachidonic acid in the body is converted to prostaglandin G.sub.2, which is subsequently converted to prostaglandin H.sub.2. Other naturally occurring prostaglandins are derivatives of prostaglandin H.sub.2. A number of different types of prostaglandins have been discovered including A, B, D, E, F,G,I and J-Series prostaglandins (EP 0 561 073 A1). Of interest in the present invention are compounds which are believed to exhibit IOP lowering mechanisms similar to those exhibited by PGD.sub.2 (a D-series prostaglandin), PGF.sub.2.alpha. (an F-series prostaglandin), and PGE.sub.2 (an E-series prostaglandin): ##STR1##
The relationship between PGD.sub.2 receptor activation and IOP lowering effects is not well understood. Various publications have reported that PGD.sub.2 receptor activation leads to second messenger activation and in particular, to the stimulation of adenylate cyclase and resultant increases in cAMP levels (Thierauch, Prostaglandins and their Receptors: II. Receptor Structure and Signal Transduction, Journal of Hypertension, 12:1-5 (1994). Regardless of the mechanism, PGD.sub.2 has been shown to lower IOP (Nakajima, Effects of Prostaglandin D.sub.2 and its analogue, BW245C, on Intraocular Pressure in Humans, Graefe's Archive Ophthalmology, 229:411-413 (1991)). Thus, it has been of interest in the ophthalmic field to develop synthetic PGD.sub.2 analogs with IOP lowering efficacy.
Synthetic PGD.sub.2 -type analogs have been pursued in the art (Nakajima, Goh, Azuma, and Hayaishi, Effects of prostaglandin D2 and its analogue, BW245C, on intraocular pressure in humans, Graefe's Archive Ophthalmology, 229:411-413 (1991)). Though PGD.sub.2 -type molecules lower IOP, these types of molecules have also been associated with undesirable side effects resulting from topical ophthalmic dosing. Such effects have included an initial increase in IOP, conjunctival hyperemia, increases in microvascular permeability, and increases in eosinophile infiltration (Alm, The Potential of Prostaglandin Derivatives in Glaucoma Therapy, Current Opinion in Ophthalmology, 4(11):44-50 (1993)).
Similarly, the relationship of PGF.sub.2.alpha. receptor activation and IOP lowering effects is not well understood. It is believed that PGF.sub.2.alpha. receptor activation leads to increased outflow of aqueous humor. Regardless of the mechanism, PGF.sub.2.alpha. and certain of its analogs have been shown to lower IOP (Giuffre, The Effects of Prostaglandin F.sub.2.alpha. the Human Eye, Graefe's Archive Ophthalmology, 222:139-141 (1985); and Kerstetter et al., Prostaglandin F.sub.2.alpha. -1-Isopropylester Lowers Intraocular Pressure Without Decreasing Aqueous Humor Flow, American Journal of Ophthalmology, 105:30-34 (1988)). Thus, it has been of interest in the field to develop synthetic PGF.sub.2.alpha. analogs with IOP lowering efficacy.
Synthetic PGF.sub.2.alpha. -type analogs have been pursued in the art (Graefe's Archive Ophthalmology, 229:411-413 (1991)). Though PGF.sub.2.alpha. -type molecules lower IOP, a number of these types of molecules have also been associated with undesirable side effects resulting from topical ophthalmic dosing. Such effects include an initial increase in IOP, breakdown of the blood aqueous barrier and conjunctival hyperemia (Alm, The Potential of Prostaglandin Derivatives in Glaucoma Therapy, Current Opinion in Ophthalmology, (11):44-50 (1993)).
The relationship between EP receptor activation and IOP lowering effects is also not well understood. There are currently four recognized subtypes of the EP receptor: (EP.sub.1, EP.sub.2, EP.sub.3, and EP.sub.4 (Ichikawa, Sugimoto, Negishi, Molecular aspects of the structures and functions of the prostaglandin E receptors, J. Lipid Mediators Cell Signaling, 14:83-87 (1996)). It is known in the art that ligands capable of EP.sub.2 receptor activation, such as PGE.sub.2 and synthetic analogs (Fallach, Eliason, Topical Prostaglandin E.sub.2 Effects on Normal Human Intraocular Pressure Journal of Ocular Pharmacology, 4(1):13-18 (1988); Woodward, et al., Molecular Characterization and Ocular Hypotensive Properties of the Prostaglandin EP2 Receptor Journal of Ocular Pharmacology and Therapeutics, 11(3):447-454 (1995)), or EP.sub.3 receptor activation (Woodward, et al., Intraocular pressure effects of selective prostanoid receptor agonists involve different receptor subtypes according to radioligand binding studies, Journal of Lipid Mediators, 6:545-553 (1993); Waterbury, et al., EP.sub.3 but not EP.sub.2 FP or TP Prostanoid-Receptor Stimulation May Reduce Intraocular Pressure, Investigative Ophthalmology and Visual Science, 31(12):2560-2567 (1990)) lower IOP. However, some of these molecules have also been associated with undesirable side effects resulting from topical ophthalmic dosing, including an initial increase in IOP, photophobia, and eye ache (see, for example, Fallach, Eliason, Topical Prostaglandin E.sub.2 Effects on Normal Human Intraocular Pressure, Journal of Ocular Pharmacology, 4(1):13-18 (1988)).
Based on the foregoing, a need exists for the development of molecules that may activate the PGD.sub.2, PGF.sub.2.alpha., and/or PGE receptors, yielding a more efficacious lowering of IOP, while exhibiting fewer or reduced side effects.
An agent which exhibits comparable or improved efficacy, but with reduced side effects when compared to other agents, is said to have an improved therapeutic profile. It is an object of this invention to provide a class of IOP lowering agents with an improved therapeutic profile over PGF.sub.2.alpha., PGD.sub.2, and PGE.sub.2 and methods of their use. It has now been discovered that the presently claimed 13-oxa analogs of prostaglandins meet this objective. 13-oxa analogs of prostaglandins have been reported in the literature (Collington, EP 0160495 A2, (1985); Mjalli, Roberts, Synthesis of Some 13-Oxaprostaglandoids, J. Chem. Soc. Perkin Trans I, 2105-2109 (1989)). The presently claimed compounds, however, and their use in IOP lowering are neither disclosed nor suggested in that art.